Synthetic Process Development of (R)-(+)-1,2-Epoxy-5-hexene: An Important Chiral Building Block

Herein, we describe two practical approaches to synthesize (R)-(+)-1,2-epoxy-5-hexene from inexpensive and readily available raw materials and reagents. The first approach is a two-step sequence, involving an epoxidation with meta-chloroperoxybenzoic acid (mCPBA) and a chiral resolution with (salen)Co(II), producing (R)-(+)-1,2-epoxy-5-hexene in 24–30% overall yield. The second approach utilizes readily available (R)-epichlorohydrin as the starting material and features an epoxide ring-opening reaction with allylMgCl and the NaOH-mediated ring closure reaction. Development of this two-step process affords R-(+)-1,2-epoxy-5-hexene in overall isolated yields of 55–60% with an exceptional purity profile. Both approaches have been successfully demonstrated on 100–200 g scales.

GC-MS Quantitative Methods.Formation of (R)-1,2-epoxyhex-5-ene (1), via Route 1 and Route 2 was monitored via GC-MS (Agilent 8890 GC-5977 MSD).The column used was an Agilent J&W HP-5ms GC Column, 30 m, 0.25 mm, 0.25 µm, 7-inch cage.The inlet was set to 250 °C.A split ratio of 50:1 was used with an injection volume of 1.0 µL.The column flow rate was 1.4 mL/min with helium as the carrier gas and an inlet pressure of 12.4 psi.The oven was initially set to 60 °C for 3 minutes, linearly ramped to 200 °C at 12 °C/min.The m/z of 67.0 was extracted from the chromatogram for quantitation.GC-FID Chiral Methods.Formation of (R)-1,2-epoxyhex-5-ene (1), via Route 1 and Route 2 was monitored via GC-MS (Agilent 6890 GC-FID).The column used was a Restek RT-GammaDEXsa (30 m x 0.25 mm x 0.25 µm).The inlet was set to 250 °C.A split ratio of 50:1 was used with an injection volume of 1.0 µL.The column flow rate was 1.4 mL/min with helium as the carrier gas and an inlet pressure of 16.4 psi.The oven was initially set to 60 °C and held for an additional 16 minutes.a All reactions were performed with 1.0 equivalent of mCPBA and 1.0 equivalent of 1,5-hexadiene.Solvent volume (V) = mL/g of 1,5-hexadiene.All these reactions were monitored by GCMS and reported as TIC A%. b Reverse addition: adding 1,5-hexadiene to a solution of mCPBA at 0°C; regular addition: 1,5-hexadiene in 5V of solvent was cooled to 0°C, to this solution was added a solution of mCPBA in 20V of the solvent.c Isolated yield after distillation.d the TIC A% in parenthesis was obtained by running the reaction for 24h.

DESIGN OF EXPERIMENTS
Design of experiments (DOE) is a valuable tool for designing the systematic table of experiments to investigate the influence of different effective factors including mCPBA/Hexadiene ratio, DCM (volume), Time (min), and Temperature (°C) on the epoxidation of 1,5-hexadiene.Three responses including GCMS TIC area percentage of chemical ( 5), (1-rac), and (7) were monitored to find the best-optimized condition of the experiment.A central composite design (CCD) from response surface methodology was used to design the experiments.CCD initializes with two levels, high and low, and then extends the levels of the factors to five by adding + , -, and center point levels.
In general, a CCD for f factors, coded as (x 1 , . . ., x f ), consists of three parts.The first part is a factorial (or cubic) design, containing a total of   = 2  points with coordinates x i = −1 or x i = +1, for i=1, ..., f.Second is an axial (or star) part formed by   = 2 ×  points with all their coordinates null except for the one that is set equal to a certain value + (or −), which usually ranges from 1 to √f.Third is a total of   runs performed at the center point of the experimental region, where x 1 =x 2 = ... =x f =0.In this study, the number of center points was 3, and a rotatable CCD with =1.68 was used to design the experiments, which resulted in 27 experiments.Table S2 shows the details about CCD factors, and their levels, and Table S3 shows the designed table of experiments.Experiment 4, in Table S3, was considered as one of the optimized conditions for epoxidation of 1,5-hexadiene with having 92% corrected assay yield based on GC-MS.In this regard, without any further multivariate optimization within the DOE experiments, one of the optimized conditions for epoxidation of 1,5-hexadiene was discovered.
Table S2.Details about CCD factors for epoxidation of 1,5-hexadiene ( 5)  a All reactions were performed with 1g of 1,5-dihexadiene, monitored by GCMS and reported as TIC A%.Solvent volume (V) = mL/g of 1,5-hexadiene.regular addition: 1,5-hexadiene in 5V of solvent was cooled to 0°C, to this solution was added solid mCPBA in one portion.
Further multivariate optimization has resulted in the six interaction terms between every two factors of A-B, A-C, A-D, B-C, B-D, and C-D that affect R2 (1-rac) are shown below (Figure S1).According to the ANOVA table: ➢ A, D, AD, and D² are significant model terms by having p-values less than 0.05 (95% confidence level) which means they are the influential factors (please see the red boxes).➢ CD and A² have p-values very close to 0.05, so they also could be considered extra-influential factors (please see the purple boxes).➢ The model is significant because its p-value is less than 0.05 which is very good and its p-value is very low (0.0017).The lower the p-value, the more significant and better (please see the green box).➢ The Lack of fit is significant because its p-value is less than 0.05 which is bad for the model and it means there is a systematic error with the model, but this is not true because it is the software's bug and drawback (please see the yellow box).The Lack of fit should not be significant and its pvalue should be greater than 0.05.The value of the p-value for the Lack of fit is the opposite of the factors and model.The software's bugs and drawbacks come from the three repeated center points.In the ideal case, the response of the three repeated center points should be the same or very close which shows repeatability but it is surprising in the software they should be a little different from each other.The experiments 11, 17, and 24 are the three center points (all factors are the same) and their corrected assay yield based on GC-MS are 54%, 55% and 55% respectively, to fix this software bug, I changed their corrected assay yield based on GC-MS to 53%, 55%, and 57% respectively, and after that I repeated the optimization.In this way, the Lack of fit is not significant because its p-value is more than 0.05.This is the proof of that, there is no systematic error in the experiments and its software bug.I put the new fake ANOVA table (yellow box) beside the true one (purple box).
➢ As it can be seen in the both ANOVA tables the p-values of other terms and the model are very similar and just the problem of the lack of fit is fixed by changing the three center points.➢ In both cases instead of the corrected assay yield based on GC-MS, the square root of the corrected assay yield based on GC-MS is modeled and Quadratic model was used.➢ As you can see the blow of the ANOVA table I put the fitting statistics.In both cases, the value of R², Adjusted R², and Predicted R² are similar.➢ The value of R² is saying that around 87% of the variance in the dependent variable that is predictable from the independent variables.However, the value of the Adjusted R² (73%) implies there should be an outlier in the experiments because of that the R² and Adjusted R² are different.The value of the Adjusted R² and Predicted R² are very more than expected different which implies there is a blocking effect in the experiments.➢ The Adeq Precision is representative of the signal to noise ration and its value around 10 is good enough to be reliable.➢ The equation in terms of coded factors can be used to make predictions about the response for given levels of each factor and with the coded equation, we can identify the relative impact of the factors by comparing the factor coefficients.
➢ As it can be seen in the coded version of the equations, the coefficients of the equation terms are very similar as well.➢ For seek of the factor importance, based on the p-values, A, D, AD, and D² were significant factors in the model and their corresponding coefficients are around -0.48, +0.33, -0.37, and -0.33.The negative and positive sign of each factor implies their negative and positive contributions respectively on the overall value of the equation.➢ The most influential factor is Factor "A" with the absolute value of 0.48, and then Factor "AD" with the absolute value of 0.37 and Factors "D" and "D²" has the same absolute value of 0.33.➢ The relative importance of the four main factors (A, B, C, D), the six interaction factors (AB, AC, AD, BC, BD, CD), the four power 2 of factors (A², B², C², D²) can be find and sort by using their coded coefficients in the above equation.For example, for the four main factors, the relative importance is A>D>B>C.
➢ It should be noted that there is probably an outlier in the system that caused the Adjusted R² to be different from R².Some statistical tests showed that experiment 25 is one of the most probable outliers which has a red circle.Experiments 10, and 17 also are two less probable ones.
➢ In following the perturbation, one factor, and two-factor interactions figures are presented.

➢
In the below figures, the predicted versus actual values are shown.
➢ According to the aforementioned results, it concludes that there was no difference between the results and figures when changing the two out of three center point values, which indicated that these results are data understanding and not data manipulation.
Table S4.Further optimization of epoxidation of 1,5-hexadiene (5) for synthesis of epoxide 1-rac a a All reactions were performed with 1.0g of 1,5-hexadiene (2.0 equivalents) and 1.0 equivalent of mCPBA with a regular addition at the temperature as indicated in the table for 3h.Solvent volume (V) = mL/g of 1,5-hexadiene.The reaction was maintained at the desired temperature using an immersion chiller.All the reactions were monitored by GCMS and reported as TIC A%. b Run at 25g scale, 50% isolated yield after distillation together with >90% of recovery of 1,5-hexadiene.

Figure S2.
Plot of the epoxidation of 1,5-hexadiene (5) performed at 150g scale of 1,5-hexadiene with 0.5 equivalent of mCPBA (210g) in three equal portions with 5V of DCM (750 mL) as a solvent.Solvent volume (V) = mL/g of 1,5hexadiene.See Experimental Procedure section and Table 1, entry 2 in the manuscript for more details.
It is worth mentioning that the control of the internal temperature of the epoxidation below 5°C was critical to minimize the formation of the diepoxide in scale.The internal temperature of the epoxidation was closely monitored as exemplified in one of the 150g scale reactions (Figure S2).The jacket temperature was setup at -10°C.consumption by crude 1 H NMR as well as a peroxide strip test.Under the condition, the utilization of 2.0 equivalents of 1,5-hexadiene ensured a complete consumption of mCPBA within 3h.
Additionally, the following quench with NaOH (2.5N) was further convinced the consumption of any remaining mCPBA.It was visualized with a clear organic and aqueous phases formation after treating with NaOH (2.5N), indicating the complete basifying of the carboxylic acid as well as any possible remaining mCPBA.And the separated organic phase was safe for the next distillation.

Reaction Clear phase separation MTBE Removal Distillation
To a 5L ChemRxnHub reactor under a nitrogen atmosphere, THF (200mL, 1V) was added followed by (R)-epichlorohydrin 6 (200g, 2.16mol, 1eq).This mixture was cooled at -25°C (internal temperature was -15.5°C) using a chiller.When the internal temperature achieved -15°C, allylmagnesium chloride 9 (1.08L, 2.16mol, 1eq, 2M in THF) was added using a peristaltic pump with a flow rate of 5-10 mL/min, maintaining the internal temperature below -5.0°C.After addition, this mixture was stirred at the same temperature for an additional 1h.Then methanol (219mL, 5.4mol, 2.5eq) was added dropwise, keeping the internal temperature below 0°C, followed by addition of HCl (2.16L, 2M, 2.0eq) at 0°C.After that, the circulating cooling system Washed by water, followed by distillation Product 1

Step 1b
Step 2b was turned off and MTBE (1L) was added.The organic layer was collected and washed with HCl (400mL, 2M) and water (400mL), respectively.This resulting organic layer (1.8L) gave an insolution yield of 91% 10 assayed by GCMS, containing 4% of dichlorohydrin 12 and 0.4% of 1,8nonadien-5-ol 11.The crude of compound 10 was used for the next step without further purification.

Representative
Chromatogram(s) (attach additional chromatograms and spectra as needed)

Figure
Figure S1.3-D plot of the primary interactions (A-B, A-C, A-D, B-C, B-D, C-D).